Systems Biochemistry in Lung Cancer: Toward a Mechanistic Understanding of NSCLC

描述（由申请人提供）：在北美和其他地方，肺癌死亡率是所有癌症中最高的，由于潜伏期长，在可预见的未来可能会保持这种情况。此外，虽然I期肺癌的5年生存率为60- 70%，但晚期疾病的预后非常差。准确检测无症状的早期肺癌风险个体目前是不可靠的。更好地了解肺癌的基本生物化学是基于机制的可靠的疾病早期检测和改进治疗方法的先决条件。转化细胞的非常复杂性，以及可变的宿主-肿瘤相互作用，使得任何单一方法都难以解决这个问题。在实验室、小鼠模型和人类受试者中在机制水平上研究肺癌的系统生物化学方法提供了解决癌症发展和进展的复杂性的机会。使用稳定同位素分辨代谢组学提供了必要的直接生化信息，肺癌与最小的处理，否则是不可用。该计划将以三管齐下的方法解决这个问题，基于以下综合项目：项目1：细胞系统生物化学。肺癌细胞的微环境营养素利用率和免疫调节。项目2：临床前系统生物化学。在人NSCLC异种移植小鼠中使用SIRM确定免疫调节剂葡聚糖的生化机制。 项目3：翻译系统生物化学。NSCLC的分子机制和SIRM对葡聚糖的反应。这三个项目将使用一种共同的机制方法来理解癌症生物化学，即我们在过去八年中一直在开发的稳定同位素分辨代谢组学（SIRM）。SIRM分析核心将满足分析要求，该核心还为三个项目提供必要的样品处理和生物信息学支持。核心A提供总体行政支助。

DESCRIPTION (provided by applicant): Deaths from lung cancer are the highest of all cancers in North America and elsewhere and, because of the long incubation time, are likely to remain so for the foreseeable future. Furthermore, although the 5-year survival rate of stage I lung cancer is 60-70%, later stage disease has a very poor prognosis. Accurate detection of asymptomatic early stage lung cancer in individuals at risk is currently unreliable. A better understanding of the basic biochemistry of lung cancers is a prerequisite to mechanism-based reliable early detection of the disease, and to improved approaches to treatment. The very complexity of the transformed cells, and the variable host-tumor interactions, makes the problem refractory to any single approach. A systems biochemistry approach in which lung cancers are studied at the mechanistic level in the laboratory, in mouse models and in human subjects offers the opportunity to address the complexity of cancer development and progression. The use of stable isotope resolved metabolomics provides the necessary direct biochemical information about lung cancer with minimal processing that is not otherwise available. This program will address the problem in a 3-pronged approach, based on the following integrated projects: Project 1: Cellular Systems Biochemistry. Microenvironmental nutrient availability and immune modulation in lung cancer cells. Project 2; Preclinical Systems Biochemistry. Using SIRM in Human NSCLC xenograft mouse to determine biochemical mechanisms of immunomodulator ¿-glucan. Project 3: Translational Systems Biochemistry. Molecular mechanisms of NSCLC and response to ¿-glucan by SIRM. The three projects will use a common mechanistic approach to understanding cancer biochemistry namely stable isotope resolved metabolomics (SIRM) that we have been developing over the last eight years. The analytical requirements will be met in the SIRM Analytical Core, which also supplies the necessary sample handling and bioinformatics support for the three projects. Core A provides overall administrative support.